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Editor,—A recent study of intestinal permeability in patients with Crohn’s disease, their spouses, and first degree relatives, has concluded that baseline permeability is influenced by environmental factors, whereas permeability provoked by acetylsalicylic acid is genetically determined (Gut1999;44:96–100). The significance of increased intestinal permeability is still unclear, but animal models show that it may be an early event in the inflammatory process, suggesting that environmental and hereditary factors interact in the pathogenesis of Crohn’s disease.

This study also observed that baseline permeability in relatives who were not living with the patient with Crohn’s disease at the time of diagnosis, or at the time of the permeability test, was considerably less abnormal than that of relatives who lived with the patient. Similarly, a subcategory of spouses who had lived with their Crohn’s disease partners since before diagnosis, had a higher percentage of increased permeability than other spouses.

Previously, increased occurrence of Crohn’s disease in a patient’s relatives has been assumed to be indicative of genetic predisposition, and has not been linked to frequency of contact. A study of clusters of cases from the same family suggested that, based on a temporal succession of presentations, an infectious microorganism might be involved.1 Several studies have proposed that spouses of patients with Crohn’s disease show a higher frequency of the disease than expected2-4; however, these studies were based on estimates of disease prevalence and could be influenced by under-reporting of such cases. Clusters of unrelated patients with Crohn’s disease who shared a close relationship or lived in the same community before developing the disease have also been reported.56

Finally, a study of disease transmission in animal models also indicated that Crohn’s disease may have an infectious aetiology. It showed consistently that animals inoculated with isolates from patients with Crohn’s disease developed chronic intestinal inflammation, whereas animals inoculated with isolates from patients with ulcerative colitis or other gastrointestinal diseases did not7; this inflammation could be prevented by addition of an antibiotic (ampicillin) to the inoculate.8

The establishment of a positive correlation between intestinal permeability in spouses and relatives and the length of association and frequency of contact with patients with Crohn’s disease could resolve whether development of the disease is due to this environmental factor. Thus, it may be useful to perform an observational study which compares the frequency, length, and nature of contact between all first degree relatives and the patient with Crohn’s disease. Soderholmet al’s study of intestinal permeability included only 34 of 123 first degree relatives of 39 patients with Crohn’s disease, because many relatives had little social contact with the patients. It is only through an exhaustive search for all relatives that frequency of contact between patients with Crohn’s disease and relatives who have the same genetic predisposition towards the disease can be linked to the risk of developing the disease. Such a study may also resolve whether earlier onset of the disease in familial cases, compared with time of onset in people who develop Crohn’s disease independently, is caused by genetic anticipation or environmental factors.

Reply

Editor,—We thank Dr Alic for his interesting comments on our study of intestinal permeability in relatives and spouses of patients with Crohn’s disease. We agree that Crohn’s disease may be part of an infectious process, and our study does not contradict this hypothesis. One of our conclusions was that baseline permeability may be a function of unknown environmental factors that could be directly related to contact with, or factors shared with, the patients with Crohn’s disease—for example, an infectious agent or dietary factors.

As Dr Alic suggests, we have further analysed the relation between length of exposure of the spouses and relatives to the patients with Crohn’s disease and baseline permeability in these people (table 1-1). We found that all spouses with an increased baseline permeability (above the 95th percentile of controls) had lived with their Crohn’s disease partner for more than 10 years. However, a study of the relatives showed that there was no link between length of time living with the patient and baseline permeability. Neither group showed any correlation between permeability after ingestion of acetylsalicylic acid and time of exposure to patients.

Number of spouses with high and low baseline intestinal permeability in relation to duration of cohabitation with patients with Crohn’s disease

We also agree that a search for all the relatives of all of our patients with Crohn’s disease would provide more information. A group from Belgium has performed a thorough study of all relatives of a group of such patients1-1; they showed increased baseline permeability in subgroups of both first degree relatives and spouses, and suggested a common environmental factor as the cause. In conclusion, we cannot exclude a transmissible factor as the cause of increased baseline permeability, although it is not known whether this accounts for permeability provoked by acetylsalicylic acid, although our data do not indicate an environmental cause.

Does the increase in baseline, and/or provoked, permeability predispose the spouse or relative towards developing Crohn’s disease? This is a different and more difficult issue to tackle. It has yet to be established whether a sustained increase in intestinal permeability can trigger inflammation, but circumstantial evidence is in favour of this as a possible mechanism. Knockout mice which are deficient in N-cadherin (an adhesion molecule important for epithelial structure) develop intestinal inflammation that resembles Crohn’s disease.1-2 Moreover, we have found that inflammation in recurrent Crohn’s ileitis is preceded by increased epithelial permeability to proteins.1-3 However, further studies are needed to explain the pathogenic importance of increased epithelial permeability to the development of mucosal inflammation in Crohn’s disease.

In the past 10 years, several studies have shown subgroups of relatives with increased baseline permeability,1-4-1-8 and four studies have shown increased mucosal reactivity to non-steroidal anti-inflammatory drugs in first degree relatives.1-9-1-12 A multicentre follow up study of the relatives included in these studies could discover whether relatives with increased baseline and/or stimulated permeability will eventually contract disease.

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